This is a resubmission of a grant application reviewed during the June 2005 study session. The revised Specific Aims are designed to meet the suggestions of the study session and to reflect the new data obtained since the original submission. The research aims at elucidating the role of vanilloid receptor TRPV1 in the sensory nerves to the joints and in the pathophysiological mechanisms of chronic osteoarthritis. TRPV1, an ion channel on nerve fibers innervating the skin, is activated by noxious heat and capsaicin, as well as by mediators of inflammation and ischemia. TRPV1-positive nerve fibers have also been discovered in a variety of subcutaneous structures, including joints, consistent with other evidence implication capsaicin-sensitive afferents in joint inflammation of clinical significance. TRPV1 is expressed by afferents in joints different from those in the skin; since joints are not normally exposed to noxious heat or capsaicin, the role of TRPV1 in articular afferents is unknown. [unreadable] [unreadable] The first aim will be determine whether TRPV1-positive articular afferents selectively contain substance P and calcitonin gene-related peptide, two neuropeptides associated with nociception in cutaneous afferents, and whether they are sensitive to nerve growth factor. The second aim will be to assess the role of TRPV1 in the neurogenic release of peptides into the synovial fluid by comparing TRPV1-null mice and wide type controls. The third aim will be to use an animal model of chronic osteoarthritis to study how genetic deletion of TRPV1 Influences the pain-related behavior, severity of inflammation, and activation of a family of extracellularly-regulated kinases (ERK) in spinal neurons. The same model will also test the hypotheses that nerve growth factor-dependent upregulation of TRPV1 in primary afferent neurons contributes to the peripheral sensitization leading to the hyperalgesia or arthritis. The fourth aim will be test the hypothesis that activation of ERK in sensory neurons helps to mediate central sensitization in osteoarthritis by testing whether this sensitization is abolished in ERK-null mice or can be prevented by intrathecal application of an inhibitor of the ERK pathway. [unreadable] [unreadable] [unreadable]